Flavone-C-glycosides from L. as possible inhibitors of phosphodiesterase-5 (PDE5): , molecular docking and molecular dynamics studies.

Phosphodiesterase-5 (PDE5) is a homodimeric enzyme that specifically targets cyclic guanosine monophosphate (cGMP), that mediates many downstream effects such as vasodilation, neurotransmission, and calcium homeostasis. Considering the functions of cGMP, inhibition of PDE5 has been established to have several therapeutic effects in disease conditions such as cancer, cardiovascular diseases and Alzheimer's disease. Consequently, many PDE5 inhibitors were developed but with severe adverse effects such as non-arteritic anterior ischemic optic neuropathy (NAION), priapism, etc. Hence, in our study for the identification of new PDE5 inhibitors from alternative sources, L. was identified as a potential PDE5 inhibitors with 56.23% inhibition at 100 μg/mL in vitro. In addition, the respective phytoconstituents were evaluated through molecular docking, interaction studies and MM/GBSA binding free energy calculations, identifying two potential flavone C-glycosides, lucenin-II (-15.977, dG bind = -38.8), stellarin-II (-15.099, dG bind = -34.59), and a flavan derivative (2S)-7,4-dihydroxyflavan(4β-8)-catechin, in comparison to sildenafil (-10.890, dG bind = -75.4) and having frequent contacts with Phe 786, Phe 820, Ser 663, Tyr 664, and other crucial residues at the catalytic site of PDE5. Molecular dynamics simulations performed for 100 ns showed structural stability and compactness of the candidates through RMSD, RMSF which showed less fluctuations. The ADMET analysis revealed favorable pharmacokinetics, and pharmacodynamic properties with no subsequent toxicity in normal cells. The biological target class prediction identified enzymes with similar properties and icariin, which is a well-established natural PDE5 inhibitor was identified as a structurally similar analogue. These findings could lead to the development of novel natural product based PDE5 inhibitors.